Cancer Medicine & Hematology · 2019. 9. 18. · E. G. I. S. T. E. R. Mandatory. p16. testing . S. T. R. A. T. I. F. Y. T Stage. 1. T1-2. 2. T3-4. N Stage. 1. N0-2a. 2. N2b-3. Zubrod

Robert Haddad, MDChief, Head and Neck Oncology Program

Dana Farber Cancer InstituteProfessor of Medicine

Harvard Medical SchoolBoston, MA

Head and Neck Cancer Thyroid Cancer

Disclosures

• Research Funding: BMS, Merck, Pfizer, Genentech, Kura

• Consultant: Merck, BMS, Eisai, Pfizer , Astra Zeneca, Genentech, Loxo, Glenmark, Immunomic, GSK

• NCCN: Member: Head and Neck Committee• NCCN: Chair: Thyroid Committee

Presente

3

Head and Neck CancerThyroid Cancer

• Introduction:Epidemiology, Clinical Features, HPV, New Staging System, Treatment Modalities

• Concurrent/Sequential/Adjuvant Chemoradiotherapy

• Recurrent/Metastatic disease: Role of Immunotherapy

• Papillary Thyroid Cancer

• Medullary Thyroid Cancer

• Anaplastic Thyroid Cancer

4

Head and Neck Cancer Primary Disease Sites

Oral Cavity

Pharynx

Larynx

Nasal Cavity

Paranasal Sinuses

Source: Maxwell V. Blum Cancer Resource Room

5

Epidemiology

• 48000 new cases per year in US.

• Median age of diagnosis: ~60 years

• Male>Female

• Strongly associated with tobacco and alcohol

• Epstein-Barr virus risk factor for nasopharynx cancers

• Human papillomavirus increasingly appreciated as a risk factor

Circular 8 kB dsDNA GenomesOnly One Coding Strand

Infect Epithelial Cells~ 200 HPV types

~ 30 Mucosal HPVsLow-Risk: Genital Warts

High-Risk: Lesions That Progress to Cancer

HPV E6/E7 OncoproteinsSmall, Non-Enzymatic Proteins

(~ 150aa E6; ~ 100aa E7)Associate With and Functionally Modify

Host Cellular Protein Complexes

HPV GENOME INTEGRATION

LCR E6 E7

Frequent Event During Malignant Progression Terminates Viral Life Cycle

Expression of E6 and E7 Is Retained

HPV-Associated Cancers

> 99% of Cervical Carcinoma~ 90% Anal Carcinomas

~ 40% Vulvar and Vaginal Carcinomas~ 60% of Oropharynx Cancers

Human Papillomavirus (HPV)

Münger et al, 2004.

6

7

Human Papillomavirus (HPV)-PositiveHead and Neck Cancer

• HPV 16 is the viral subtype in the vast majority of patients.

• Half of oropharynx cancers will have HPV 16 DNA. • Often occurs in nonsmokers, nondrinkers• Median age younger than HPV-negative patients;

incidence increasing• Associated with ↑ number of sexual partners and high-

risk sexual practices • Favorable prognosis• In situ hybridization,p16 IHC, PCR

Fakhry C, et al. J Clin Oncol. 2006:24(17):2606-2617. Chaturvedi AK, et al. J Clin Oncol. 2008;26(4):612-619.

RTOG 0129 Phase III Trial: Concomitant CRT With Standard Vs. Accelerated Fractionation RT

Survival Outcomes by HPV Status

Stage III/IV (T2, N2–3, M0, or T3–4, any N, M0) SCCHN Oral cavity, oropharynx,

hypopharynx, larynx No prior RT to head and neck

except radioactive iodine therapy

No prior surgery to primary tumor or nodes except for diagnostic biopsy

Expected N = 720

Cisplatin(IV on D1, 22, 43)Standard fractionation RT(5 d/wk for 7 wks)

CRT

RANDOMIZE

Cisplatin(IV on D1, 22)Accelerated fractionation RT(5 d/wk for 3.5 wks; then twice daily, 5 d/wk for 2.5 wks)

US NIH, 2010c. Ang et al NEJM 2010

RTOG 0129: OS and PFS by HPV Status

Ang. N Engl J Med. June 7, 2010

3-Year Outcomes HPV Positive (%) HPV Negative (%) P ValueOS 82.4 57.1 <0.001PFS 73.7 43.4 <0.001Locoregional failure 13.6 35.1 <0.001Distant metastases 8.7 14.6 0.23

PFSOverall Survival100

75

50

25

0

100

75

50

25

0

Ove

rall

Surv

ival

(%)

Prog

ress

ion-

Free

Sur

viva

l (%

)

HPV negativeHPV positive

HPV negativeHPV positive

HR=0.38 (95% CI:0.26-0.55); P<0.001

HR=0.40 (95% CI:0.29-0.557; P<0.001

Two distinct HNSCC entities

HPV positive HPV negative

Anatomic site Tonsil /Base of Tongue All sites

Histology Basaloid Keratinized

Age Younger Older

Gender 3:1 men 3:1 men

SE status High Low

Risk factors Sexual behavior ETOH/tobacco

Cofactors Marijuana/?immune suppression

ETOH/tobacco

Incidence Rising Declining

Survival Improved Worse

There is a major change in the etiology of head and neck cancer, the incidence of OPC rapidly increasing mostly North America and Europe

should we treat them the same ?

Major changes in clinical vs. pathologic N staging, for p16+ HNC

• N0 No node metastasis• N1 Ipsilateral nodes, ≤6

cm• N2 Contralateral/bilateral

nodes, ≤6 cm • N3 Node >6 cm

No more N2a, N2b, N2c

Clinical system

• pN0 No node metastasis

• pN1 ≤4 nodes

• pN2 >4 nodes

Pathologic systemvs

Clinical ENE is not staged for p16+ OPC

Oropharynx Clinical Stage Grouping, 8th ed.

cN0 cN1 cN2 cN3cT0 I I II IIIcT1 I I II IIIcT2 I I II IIIcT3 II II II IIIcT4 III III III III

P16+ NEW

cN0 cN1 cN2 cN3cT1 I III IVA IVBcT2 II III IVA IVBcT3 III III IVA IVB

cT4a IVA IVA IVA IVBcT4

b IVB IVB IVB IVB

P16- UNCHANGED

M1 = stage IV

M1 = stage IVC

AJCC 8—Highlights Summary

• Recognition of New Disease: HPV+ Oropharynx Cancer– Also Separate Clinical and Pathological Systems

• Modification of T Stage For Oral Cavity, Depth of Invasion(DOI)

• HPV- Neck: Include ENE; Clinical & Path • Unknown Primary

14

Treatment Approach

Disease Extent Treatment

T1N0-1 or T2N0 Surgery or RT

T2N1 or T3-4 or N2-3 Combined modality

Recurrent or M1 Surgery and/or RTCombined modalityChemotherapy

Concurrent Chemoradiotherapy

16

The Debate Over Therapeutic Sequence: MACH-NC Findings

MACH-NC: Meta-Analysis of Chemotherapy in Head and Neck Cancer; PF=cisplatin + fluorouracil1. Pignon JP, et al. Lancet. 2000;355(9208):949-955. 2. Monnerat C, et al. Ann Oncol. 2002;13(7):995-

1006..

Design(No. of Studies/No. of Subjects)

Hazard Ratio(95% CI)

ChemotherapyEffect

(P -value)

Absolute Benefit

2 Years 5 Years

Adjuvant1

(8/1854)0.98

(0.85-1.19) 0.74 1% 1%

Neoadjuvant1

(31/5269)0.95

(0.88-1.01) 0.10 2% 2%

Concurrent1

(26/3727)0.81

(0.76-0.88) < 0.0001 7% 8%

Total1(65/10,850)

0.90(0.85-0.94) < 0.0001 4% 4%

No. of Trials No. of Subjects Difference at 5 Years P -value

PF induction2 15 2487 5% 0.01

Concurrent Therapy: Standard of Care

• RT standard fractionation, 70 Gy over 7 weeks (2-Gy fractions)

• Alternative Chemotherapy regimens: 1- Weekly cisplatin 40mg/m22- Weekly Cetuximab3- Weekly carboplatin auc 1.5-2+Paclitaxel 30-45mg/m2

• Cisplatin 100 mg/m2 days 1, 22, and 43 of RT

18

RTOG 91-11 Induction Cisplatin/5-FU vs Concomitant Cisplatin vs RT Alone in

Resectable SCC

Forastiere AA, et al. N Engl J Med. 2003;349(22):2091-2098.

Resectable stage III/IV SCC

• Glottic or supraglottic cancer

• Previously untreated

N = 515

Cisplatin (100 mg/m2, d1)5-FU (1000 mg/m2/day, d1-5 C-I)

every 3 wks, 2 cycles

CRT (N = 171)

RANDOMIZE

ICTRT (N = 173)

Cisplatin (100 mg/m2, every 3 wks, 3 cycles)

RT (2 Gy/fr, 35 fr, total 70 Gy)

RT (2 Gy/fr, 35 fr, total 70 Gy)RT (N = 171)

RT(2 Gy/fr, 35 fr, total 70 Gy)

• Primary end point: larynx preservation • Secondary end point: LFS

LFS=laryngectomy-free survival

19

RTOG 91-11Larynx Preservation (LP) Trial

Arm Stomatitis* LP rate (5yrs) DFS (5yrs)

OS (5yrs)

RT 24% 65.7% 27.3% 53.5%

Chemo RT 24% 70.5% 38.6% 59.2%

ChemoRT 43% 83.6% 39.0% 54.6%

* > or = Grade 3

.Forastiere AA, et al. N Engl J Med. 2003;349(22):2091-2098.

20 Bonner JA, et al. N Engl J Med. 2006;354(6):567-578.

Phase III Trial: Cetuximab + RT for SCC

Advanced SCC• Stage III/IV• N = 424

RT*+

Cetuximab (400 mg/m2, then 250 mg/m2/wk)

RANDOMIZE

RT* alone

*Choice of: • Once-daily RT: 70 Gy in 35 fractions• Twice-daily RT: 72.0-76.8 Gy in 60-64 fractions• Concomitant boost: 72 Gy in 42 fractions

Grade 3-5 ToxicityRT Alone (N = 212)

RT + Cetuximab (N = 208) P-value

Mucositis 52% 56% .44

Acneiform Rash 1% 17% < .001

Infusion Reaction 0% 3% .01

Anemia 6% 1% .006

21Bonner JA, et al. N Engl J Med. 2006;354(6):567-578.

Phase III: Cetuximab + RT for SCC: Results

47% vs 34% at 3 yearsP < .01 at 3 years

55% vs 45% at 3 yearsP = .05 at 3 years

Locoregional Control OS

NRG-RTOG 1016: Phase III Trial Comparing Radiation/Cetuximab to Radiation/Cisplatin in

HPV-Related Cancer of the Oropharynx

Gillison et al : Lancet . January 2019

R

E

G

I

S

T

E

R

Mandatory

p16

testing

S

T

R

A

T

I

F

Y

T Stage1. T1-22. T3-4

N Stage1. N0-2a2. N2b-3

ZubrodPerformance Status1. 02. 1

Smoking History1. ≤ 10 pack-years2. > 10 pack-years

R

A

N

D

O

M

I

Z

E

Arm 1 (Control):Accelerated IMRT, 70 Gy for 6 weeks+ high dose cisplatin (100 mg/m2) Days 1 and 22(Total: 200 mg/m2)

Arm 2:Accelerated IMRT, 70 Gy for 6 weeks+ cetuximab (400 mg/m2) loading dose pre-IMRT,then 250 mg/m2 weekly during IMRT,+ 1 week after IMRT for a total of 8 doses ofcetuximab

Phase III Trial of Radiotherapy plus Cetuximab versus Chemoradiotherapy in HPV-Related Oropharynx Cancer

RTOG 1016 HPV Trial

Patient and Tumor Characteristics

• 805 patients analyzed • Median age 58 • 90% male; 93% white• 74%/26% Zubrod 0/1• 38% >10 pack-years smoking• T4 disease 12%• 90% N2-3 (AJCC 7th edition)

RTOG 1016 HPV Trial

Overall Outcomes

Hazard ratio (cetuximab/cisplatin): 1.451-sided 95% upper confidence bound: 1.94

Cisplatin Cetuximab

Overall Survival (5 yr) 85 vs 78 % (p=0.02)Progression-free (5 yr) 78 vs 67 (p<0.001)LRF (5 yr) 10 vs 17 (p<0.001)

RTOG 1016 HPV Trial

Overall Survival

RTOG 1016 HPV Trial

Cisplatin

85 vs 78% 5-yr

p-value (non-inferiority) 0.51

p-value (1-sided log-rank test) 0.02

Conclusions

• Non-inferiority of cetuximab was NOT demonstrated

• Cisplatin had better OS, PFS, LRC

• “Classical” Overall Acute Toxicity: no difference

• Acute “Toxicity Burden”: 40% worse with cisplatin

• Late “Toxicity Burden”: 40% worse with cisplatin

RTOG 1016 HPV Trial

Sequential Chemoradiotherapy

29

TAX 324: Sequential Combined Modality TherapyTPF vs PF Followed by Chemoradiotherapy

RANDOMIZE

P

P

F

F

Carboplatinum - AUC 1.5 Weekly

Daily Radiotherapy

T

TPF: Docetaxel 75D1 + Cisplatin 100D1 + 5-FU 1000 CI- D1-4 Q 3 weeks x3 PF: Cisplatin 100 D1 + 5-FU 1000 CI-D1-5 Q 3 weeks x 3

Surgery as

Needed

Posner MR, et al. N Engl J Med. 2007;357(17):1705-1715.

TAX 324: Results

TPF significantly improves survival and PFS compared with PF in an ICT regimen followed by CRT

Posner et al, 2007.

TPF 62%PF 48%

TPF 67%PF 54%

Log-rank p = .0058HR = 0.70

TPF 53%PF 42% TPF 49%

PF 37%

Log-rank p = .004HR = 0.701

Survival PFS

Time (mos)

Surv

ival

Pro

babi

lity

(%)

0 6 12 18 24 30 36 42 48 54 60 66 72

0

10

20

30

40

50

60

70

80

90

100

TPF (N = 255)

PF (N = 246)

Time (mos)PF

S Pr

obab

ility

(%)

0 6 12 18 24 30 36 42 48 54 60 66 72

0

10

20

30

40

50

60

70

80

90

100

TPF (N = 255)

PF (N = 246)

TPF significantly improves survival and PFS compared with PF in an ICT regimen followed by CRT

Posner. N Engl J Med. 2007;357:1705

31

Conclusions

• Overall survival advantage > 3 years with TPF sequential therapy– 40.5 month improvement in median overall survival at 3 years– 30% reduction in the risk of mortality (P = 0.0058)

• Consistent with prior phase III trial (TAX 323)

• Patients received a median of 3 cycles of induction chemotherapy in the TPF and PF arms.

• In the TPF arm, 81% of patients went on to receive CRT.

• Grade 3/4 treatment-emergent adverse events:– Less stomatitis, thrombocytopenia, and lethargy in the TPF arm– More neutropenia and febrile neutropenia (any grade) in the TPF

arm

32

Impact of Induction Chemotherapy (CT):Opposing Views and Ongoing Controversy

• Pro: Allows time to optimize patient medical status; Possible customization of RT dosing based on response to treatment; provides early treatment of distant micrometastatic disease

• Con: Induction CT may affect adversely compliance to subsequent concurrent CT/RT or choice of CT/RT regimen; adds 2-4 months to treatment

33

Clinical Scenarios to Consider Induction Therapy

1. Potential distant metastasis2. Delay in radiation simulation3. Impending local issue (eg, airway)4. Markedly advanced disease (eg, bulky, N2c, N2b,

N3, low neck, dermal infiltration)5. Organ preservation strategy in patients with markedly

advanced disease

34

Neck Dissection (ND)After Chemoradiotherapy

• Indicated for gross residual disease• Not indicated for pretreatment N1 disease that has

achieved clinical complete response • For pretreatment N2-3 disease, opinions vary:

– When pretreatment neck disease is N2-3, some centers recommend routine ND regardless of response to chemoradiotherapy.

– However, others will observe if a clinical complete response on PET scan 12 weeks post-therapy is achieved with chemoradiotherapy.

Pellitteri PK, et al. Head Neck. 2006;28(2):166-175. Ong SC, et al. J Nucl Med. 2008;49(4):532-540.

Adjuvant Chemoradiotherapy

36

EORTC 22931 and RTOG 9501 Phase III Trials: Adjuvant RT ± Concomitant Cisplatin

Bernier J, et al. N Engl J Med. 2004;350(19):1945-1952. Cooper JS, et al. N Engl J Med. 2004;350(19):1937-1944.

Resectable SCC• Oral cavity, oropharynx, hypopharynx,

larynx• Stage III/IV (EORTC), high risk (RTOG)• Previously untreated

N = 334 (EORTC)N = 459 (RTOG)

Surgery

RANDOMIZE

RT+Cisplatin (100 mg/m2, d1,22,43)

EORTC: 66 Gy over 6.5 wksRTOG: 60-66 Gy over 6-6.6 wks

37

Poor Risk Criteria

RTOG 95011

≥ 2 nodesECE +Margins

EORTC 229312

Level IV/V (OC/OP)ECE+MarginsPerineural diseaseVascular emboli

ECE = extracapsular nodal extension; OC = oral cavity; OP = oropharynx

1. Cooper JS, et al. N Engl J Med. 2004;350(19):1937-1944.2. Bernier J, et al. N Engl J Med. 2004;350(19):1945-1952.

38

OS (EORTC)1 OS (RTOG)2

EORTC 22931 and RTOG 9501: Adjuvant RT ±Concomitant Cisplatin: Results

P=0.02P=0.19

Months After Randomization

1. Bernier J, et al. N Engl J Med. 2004;350(19):1945-1952. 2. Cooper JS, et al. N Engl J Med. 2004;350(19):1937-1944.

39

RTOG 9501/EORTC 22931Which prognostic risk factors are most important?

• Extracapsular nodal extension and + margins: significant benefit from chemoradiotherapy

• Trend toward benefit for stage III-IV disease, perineural invasion, vascular embolisms, and/or clinically enlarged level IV/V lymph nodes secondary to tumors in oral cavity or oropharynx

• No benefit in patients with 2 or more nodes but no extracapsular extension

Bernier J, et al. Head Neck. 2005;27(10):843-850.

40

Survivorship /Follow-Up

• Assess for recurrence/2nd primary/premalignant lesions– 1st year: Q 1-3 mos– 2nd year: Q 2-4 mos– 3rd – 5th year: Q 4-6 mos– > 5 years: Q 6-12 mos

• TSH q 6-12 months if neck irradiated• Chest imaging as indicated• Speech/Swallowing evaluation/rehabilitation as indicated• Counsel regarding tobacco and alcohol use• Integrate general medical care• Once felt disease free, imaging of primary and neck not routinely

indicated unless suspicious signs or symptoms

NCCN Clinical Practice Guidelines in Oncology. Head and Neck Cancers. V.2.2010. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp.

Palliative Chemotherapy

Management of Recurrent/Metastatic SCCHN

Salvage surgery or re-irradiation

Palliative systemic therapy

Supportive care

Chemotherapy +/-Targeted Therapy

Immunotherapy

Clinical Trials

Rec

urre

nt/ M

etas

tatic

HN

SCC

43

EXTREME: Study Design

5-FU 1000 mg/m2 d1-4withCisplatin 100 mg/m2 d1orCarboplatin AUC 5 d1plusCetuximab 250 mg/m2/week*q 3 weeks

*Loading dose of 400 mg/m2 on week 1

RANDOMIZE

N = 442

5-FU 1000 mg/m2 d1-4withCisplatin 100 mg/m2 d1orCarboplatin AUC 5 d1

Notreatment

6 cycles maximum

POD ortoxicity

POD ortoxicity

Cetuximab

Vermorken JB, et al. N Engl J Med. 2008;359(11):1116-1127.

44

EXTREME: First-Line Platinum/5-FU ± Cetuximab in Recurrent/Metastatic SCC: Survival

10.1 mos7.4 mos

Survival Time (months)Patients at Risk:Platinum/5-FU

Cetuximab + Platinum/5-FU220 173 127 83 65 47 19 8 1222 184 153 118 82 57 30 15 3

HR (95% CI)=0.797 (0.644-0.986)Strat. log-rank test: 0.0362

Platinum/5-FUCetuximab + Platinum/5-FU

Surv

ival

Pro

babi

lity

0.00.10.20.30.40.50.60.70.80.91.0

0 3 6 9 12 15 18 21 24

OS RR18%35%

Vermorken JB, et al. N Engl J Med. 2008;359(11):1116-1127.

Immunotherapy in Head and Neck Cancer

Protocol-Specified Final Results of the KEYNOTE-048 Trial of Pembrolizumab as First-Line Therapy for Recurrent/ Metastatic Head and Neck Squamous Cell Carcinoma (R/M HNSCC)

Presented By Danny Rischin at 2019 ASCO Annual Meeting

KEYNOTE-048 Study Design (NCT02358031)


Study End Points: Pembrolizumab vs EXTREME and Pembrolizumab + Chemotherapy vs EXTREME


Baseline Characteristics, ITT Population




OS, P+C vs E, CPS ≥20 Population


OS, P+C vs E, CPS ≥1 Population


OS, P+C vs E, Total Population




OS, P vs E, Total Population


OS, P vs E, CPS ≥20 Population


OS, P vs E, CPS ≥1 Population


Summary and Conclusions


CheckMate 141 Study DesignNivolumab VS. Chemotherapy

R2:1

Nivolumab3 mg/kg IV q2w

Investigator’s Choice • Methotrexate 40 mg/m²

IV weekly• Docetaxel 30 mg/m² IV

weekly• Cetuximab 400 mg/m² IV

once, then 250 mg/m² weekly)

Key Eligibility Criteria

• R/M SCCHN of the oral cavity, pharynx, or larynx

• Not amenable to curative therapy • Progression on or within 6 months of

last dose of platinum-based therapy• ECOG PS 0–1• Documentation of p16 to determine

HPV status • No active CNS metastases

Stratification factor• Prior cetuximab treatment

CNS, central nervous system; DOR, duration of response; ECOG PS, Eastern Cooperative Oncology Group performance status; HPV, human papillomavirus; ORR, objective response rate; OS, overall survival; PFS, progression-free survival; R, randomized; R/M, recurrent/metastatic; SCCHN, squamous cell carcinoma of the head and neck; Clinicaltrials.gov. NCT02105636.

Primary endpoint• OS

Other endpoints• PFS• ORR• Safety• DOR• Biomarkers• Quality of life

Randomized, global, phase 3 trial of the efficacy and safety of nivolumab versus investigator’s choice in patients with R/M SCCHN

Ferris et al : NEJM 2016

0 3 6 9 12 15 18

Median OS, mo (95% CI)

HR(97.73% CI) p-value

Nivolumab (n = 240) 7.5 (5.5–9.1) 0.70 (0.51–0.96) 0.0101

Investigator’s Choice (n = 121) 5.1 (4.0–6.0)

Overall Survival

Months

Nivolumab 240 167 109 52 24 7 0

Investigator’sChoice

121 87 42 17 5 1

No. at Risk

0

0

10

20

30

40

50

60

70

80

90

100

Ove

rall

Surv

ival

(% o

f pat

ient

s)

1-year OS rate (95% CI)36.0% (28.5–43.4)

16.6% (8.6–26.8)

Phase 3 KEYNOTE-040 Study Pembrolizumab vs Chemotherapy

Key Eligibility Criteria• SCC of the oral cavity, oropharynx,

hypopharynx, or larynx• PD after platinum-containing regimen

for R/M HNSCC or recurrence or PD within 3-6 mo of multimodal therapy using platinuma

• ECOG PS 0 or 1• Known p16 status (oropharynx)b

• Tissue samplec for PD-L1 assessmentd

Pembrolizumab 200 mg IV Q3W

for 2 y

Stratification Factors• ECOG PS (0 vs 1)• p16 statusb (positive vs negative)• PD-L1 TPSd (≥50% vs <50%)

Methotrexate 40 mg/m2 QWe

ORDocetaxel 75 mg/m2 Q3W

ORCetuximab 250 mg/m2 QWf

R 1:1

• Clinically stable patients with radiologic PD could continue treatment until imaging performed ≥4 wk later confirmed PD

• Crossover not permitted

aLimit of 2 prior therapies for R/M HNSCC. bAssessed using the CINtec p16 Histology assay (Ventana); cutpoint for positivity = 70%.cNewly collected preferred. dAssessed using the PD-L1 IHC 22C3 pharmDx assay (Agilent Technologies). TPS = tumor proportion score = % of tumor cells with membranous PD-L1 expression. eCould be increased to 60 mg/m2 QW in the absence of toxicity. fFollowing a loading dose of 400 mg/m2.

0 5 1 0 1 5 2 0 2 5 3 00

1 02 03 04 05 06 07 08 09 0

1 0 0

T im e , m o n th s

OS

, %

N o . a t r is k2 4 7 1 5 9 1 0 3 48 14 2 02 4 8 1 4 8 82 34 10 1 0

1 2

Overall Survival in ITT Population

aCox proportional hazards model with treatment as a covariate stratified by the randomization stratification factors. Initially reported data: HR 0.82 (95% CI, 0.67-1.01), P = 0.0316. After the initial report, updated survival data were obtained for 4 patients. bOne-sided P value based on the log-rank test stratified by the randomization stratification factors. Data cutoff date: May 15, 2017.

37.3%27.2%

8.4 mo (6.5-9.4)7.1 mo (5.9-8.1)

Median (95% CI)

Events, n HR (95% CI) PPembrolizumab 179 0.81a (0.66-0.99) 0.0204b

SOC 201

RAI-Refractory Thyroid Carcinoma

Advanced Thyroid Cancer

Patients with advanced, progressive thyroid carcinoma that is refractory to radioactive iodine (RaI) have few treatment options.

All types of thyroid carcinoma (papillary, follicular, medullary, and anaplastic) are poorly responsive to traditional systemic chemotherapy.

A number of targeted agents are now approved or under investigation in this patient population

Radioactive-Iodine (RAI)-Refractory Differentiated Thyroid Cancer (DTC)

• It is estimated that in the USA in 2013 there will be: – >60 000 new cases of thyroid cancer, and

– 1850 deaths due to thyroid cancer

• In approximately 5–15% of patients with thyroid cancer, the disease becomes refractory to RAI

• Median survival for patients with RAI-refractory DTC and distant metastases is estimated to be 2.5–3.5 years

• Patients often suffer multiple complications associated with disease progression

• Sorafenib approved in USA in 2013 based on DECISION trial • Lenvatinib approved in USA in 2015 based on SELECT trial

1. Howlader N et al. SEER Cancer Statistics Review; http://seer.cancer.gov/statfacts/html/thyro.html; 2. Xing M et al. Lancet 2013; 381:1058–69; 3. Pacini F et al. Expert Rev Endocrinol Metab 2012;7:541–54; 4. Durante C et al. J Clin Endocrinol Metab 2006;91:2892–99. 5. Robbins RJ et al. J Clin Endocrinol Metab 2006;91:498–505. 5. Brose et al Lancet. 2014 Apr 23.

Sorafenib in Locally Advanced or Metastatic Patients with Radioactive Iodine-refractory

Differentiated Thyroid Cancer

The Phase 3 DECISION Trial

Brose et al : Lancet. 2014 Apr 23

• Stratified by– Geographical region (North America, Europe, Asia) – Age (<60, ≥60 years)

• Progression assessed by independent central review every 8 weeks • At progression:

– Patients on placebo allowed to cross over at the investigator’s discretion – Patients on sorafenib allowed to continue on open-label sorafenib at the investigator’s discretion

DECISION Trial: Study Design

N=417 randomized from Nov 2009 to Aug 2011

• Locally advanced or metastatic, RAI-refractory DTC

• Progression (RECIST) within the previous 14 months

• No prior chemotherapy, targeted therapy, or thalidomide

Primary endpoint• PFS

Secondary endpoints• OS• Response rate• Safety• Time to progression • Disease control rate • Duration of response

Sorafenib400 mg orally

twice daily

RANDOMIZATION

1:1

Placebo orally twice

daily

Brose M, et al. Lancet. 2014;384:319-328.

DECISION Trial: Progression-Free Survival

nMedian PFS,

Days (Months)Sorafenib 207 329 (10.8)

Placebo 210 175 (5.8)

PFS

Prob

abili

ty, %

Days From Randomization0 100 200 300 400 500 600 700 800

HR=0.587; 95% CI: 0.454-0.758; P<0.0001

01020

40

60

80

100

30

50

70

90


At progression:• 150 patients on placebo (71%) received open-label sorafenib• 55 patients on sorafenib (27%) received open-label sorafenib

69

DECISION Trial: Overall Survival

01020

40

60

80

100

30

50

70

90

0 100 200 300 400 500 600 700 800 900 1000

Median OS

Sorafenib Not reached

Placebo Not reached

HR=0.802 (95% CI: 0.539-1.194)P=0.138, one-sidedSu

rviv

al P

roba

bilit

y, %

Days From Randomization


70

DECISION Trial: Response Rates

Endpoints Sorafenib Placebo P ValueTotal evaluable patients, n (%) 196 201Response rate, n (%) 24 (12.2) 1 (0.5) <0.0001

Complete response 0 0 –Partial response 24 (12.2) 1 (0.5) –

Stable disease for ≥6 months, n (%) 82 (41.8) 67 (33.2) –

Disease control rate (CR + PR + SD ≥6 months), n (%) 106 (54.1) 68 (33.8) <0.0001

Median duration of response (PRs) (range), months 10.2 (7.4-16.6) NA –


SELECT TrialStudy of (E7080) LEnvatinib in

Differentiated Cancer of the Thyroid (SELECT)

Schlumberger M et al : NEJM 2015

• Stratified by– Geographic region (Europe, North America, other)– Prior VEGF-/VEGFR-targeted therapy (0, 1)– Age (≤65, >65 years)

72

SELECT Trial : Study Design

Global, randomized, double-blind, phase III trial

Patients with DTC (N=392)

• IRR evidence of progression within previous 13 months

• 131I-refractory disease• Measurable disease• Up to 1 prior VEGF- or

VEGFR-targeted therapyLenvatinib

(optional, open-label)

Primary endpoint• PFS

Secondary endpoints• ORR• OS• Safety

Lenvatinib (n=261)24 mg daily po

RANDOMIZATION

Placebo (n=131)24 mg daily po

Treatment until disease progression

confirmed by IRR(RECIST v1.1)

IRR=independent radiologic review; ORR=objective response rate; RECIST=Response Evaluation Criteria in Solid Tumors.

SELECT Trial: Primary Endpoint,Kaplan-Meier Estimate of PFS

Median PFS (95% CI), Months

Lenvatinib 18.3 (15.1-NR)

Placebo 3.6 (2.2-3.7)

HR (99% CI): 0.21 (0.14-0.31)Log-rank test: P<0.0001

Progression events, 41%

Progression events, 86%

Prog

ress

ion-

Free

Sur

viva

l, Pr

opor

tion

Time, MonthsNumber of patients at risk:LenvatinibPlacebo

261131

22571

19848

17629

15919

14818

13611

925

664

442

242

112

30

00

NR=not reached.Schlumberger M, et al. NEJM 2015

SELECT Trial: PFS by Previous VEGF-Targeted Therapy

Time, Months

Time, Months

Prog

ress

ion-

Free

Su

rviv

al, P

ropo

rtio

n 1.00.90.80.70.60.50.40.30.20.10.0

0 2 4 6 8 10 12 14 16 18 20 22 24 26

No Previous VEGF-Targeted Therapy (n=299)

1.00.90.80.70.60.50.40.30.20.10.0

0 2 4 6 8 10 12 14 16 18 20 22 24 26

Previous VEGF-Targeted Therapy: 1 Line (n=93)

Lenvatinib 195 167 148 135 123 116 108 72 52 34 20 11 3 0Placebo 104 56 36 25 17 12 10 4 3 1 1 1 0 0

Number of patients at risk:

Lenvatinib 66 58 50 41 36 32 28 20 14 10 4 0 0 0Placebo 27 15 7 4 2 1 1 1 1 1 1 1 0 0

Number of patients at risk:

Prog

ress

ion-

Free

Su

rviv

al, P

ropo

rtio

nMedian PFS

(95% CI), Months


Placebo 3.6 (2.1-5.3)


Median PFS (95% CI), Months


Placebo 3.6 (1.9-3.7)


SELECT Trial: OS, ITT Population

Number of subjects at risk:

No significant difference was observed in the RPSFT‐adjusted OS

(secondary endpoint; P=0.051), which was used to correct for a potential crossover effect in the placebo arm

Lenvatinib 261 248 239 230 219 211 203 169 114 78 55 22 10 3 0Placebo 131 126 126 118 108 103 96 78 53 39 23 8 2 1 0

Time, Months

Ove

rall

Surv

ival

, Pro

port

ion

1.0

0.9

0.8

0.7

0.6

0.5

0.4

0.3

0.2

0.1

0.00 2 4 6 8 10 12 14 16 18 20 22 24 2826

Median OS (95% CI), Months

Lenvatinib NR (22.0-NR)Placebo NR (20.3-NR)

ITT=intent-to-treat; IRR=independent radiologic review; RPSFT=rank-preserving structural failure time.Schlumberger M, et al. NEJM 2015

• 109 (95.6%) of 114 eligible placebo patients received open-label lenvatinib post progression

SELECT Trial: Response Rates

Lenvatinib(n=261)

Placebo(n=131)

ORR, n (%) 169 (65) 2 (2)[95% CI] [59.0-70.5] [0.0-3.6]P value <0.0001

Complete response, n (%) 4 (2) 0Partial response, n (%) 165 (63) 2 (2)Stable disease ≥23 weeks, n (%) 40 (15) 39 (30)Progressive disease, n (%) 18 (7) 52 (40)Median time to objective response (95% CI), months* 2.0 (1.9-3.5) –

Duration of response (95% CI), months* NR (16.8-NR) –

*Nonresponders were not included in the median time to response assessment.Schlumberger M, et al. NEJM 2015

NCCN Guidelines: Recurrent/Metastatic disease not amenable to RAI

Papillary, Follicular. Hurtle cell Carcinomas

• First Line: Consider Lenvatinib (preferred) or Sorafenib for progressive and/or symptomatic disease

• Subsequent therapy: Consider other TKI’s on further progression (everolimus, vandetanib, cabozantinib, vemurafenib, axitinib, sunitinib, pazopanib)

• Consider local therapies: Surgery, cryotherapy, Ethanol ablation, radiation therapy

• Active surveillance when appropriate • Biphosphonate or Denosumab (If Bone metastasis) • Radiation , Surgery (Brain metastatsis)

Medullary Thyroid Cancer

Derived from parafollicular C-cells

Markers : CEA, CTN

Metastatic disease frequently affecting mediastinum, lung, bone and liver.

Two agents approved in US : Vandetanib Cabozantinib

Courtesy Drs Justine Barletta/Cheryl Adackapara

Vandetanib in Medullary Thyroid Cancer:ZETA Trial

• Phase III, double-blind, placebo-controlled study•

• 331 patients with advanced MTC

• Measurable disease (no progression required), Calcitonin level >500pg/ml

• Vandetanib 300mg (n=231) or placebo (100)

• Cross-over allowed

• Primary endpoint: Progression free survival

Wells S A et al. JCO 2012;30:134-141

•54% reduction in the rate of progression (HR=0.46, p=0.0001)

Wells S A et al. JCO 2012;30:134-141



•PFS NR in Vandetanib arm, 19.3m for placebo

Wells S A et al. JCO 2012;30:134-141



Wells S A et al. JCO 2012;30:134-141

P=0.0001




•Objective response rate (ORR) 45% versus 13% (p<0.0001)

Wells S A et al. JCO 2012;30:134-141

P=0.0001


Cabozantinib in Medullary Thyroid Cancer :EXAM Trial

Treatment until progression or unacceptable toxicity

Locally advanced or metastatic

MTC with documented

RECIST progression

Cabozantinib 140 mg

Placebo

2:1 Randomization

PRO

GR

ESSI

ON

Survival follow-up

No Cross-OverNo Unblinding

Elisai et al : JCO 2014

• Randomized, placebo-controlled study• 330 patients with locally advanced or metastatic MTC • Documented RECIST progressive disease within 14 months of

screening• No limit on prior therapy• Primary endpoint PFS

PFS: 11.2 versus 4.0 months (HR 0.28 95%CI 0.19-0.4 p<0.0001)

Cabozantinib in Medullary Thyroid Cancer :EXAM Trial

Elisai et al : JCO 2014

NCCN Guidelines MTC: Recurrent/Metastatic disease

• First Line: Consider Vandetanib or Cabozantinib for progressive and/or symptomatic disease.

• Subsequent therapy: Consider other TKI’s on further progression (Sorafenib, Lenvatinib, sunitinib, pazopanib)

• Dacarbazine based chemotherapy. • Do NOT treat based on CEA /CTN levels alone. • Consider local therapies.• Active surveillance when appropriate. • Biphosphonate or Denosumab (If Bone metastasis) • Radiation , Surgery (Brain metastatsis)

Typically a tumor of older adults

Presence of pre-existing or co-existing well differentiated carcinoma in 23-78% of cases, usually papillary TC

History of long-standing goiter frequent.

Clinical presentation: Rapidly growing neck mass, hoarseness, vocal cord paralysis,dysphagia

Early hematogenous metastasis

Spindle cell patternPleomorphic giant cell patternSquamoid pattern

Anaplastic Thyroid Cancer

Courtesy Drs Justine Barletta/Cheryl Adackapara

Dabrafenib Plus Trametinib in BRAF V600E-Positive ATC

.Subbiah et al, 2017.

Design

• Multicenter, open-label, phas e 2 in rare B R AF V6 0 0 E -pos cancers (AT C, biliary tract cancer, Gr 1 / 2 and 3 / 4 glioma, adeno CA s mall intes tine, hairy cell leukemia, and multiple myeloma)

• 1 6 AT C patients included• Dabrafenib 1 5 0 mg bid plus trametinib 2 mg daily P O• P rimary end point: res pons e rate

R es ults

• All patients had received prior R T , 6 w/ prior line of s ys temic therapy• Median follow up of 4 7 weeks• R es pons e rate 6 9 % (1 1 / 1 6 )• Median s urvival, P FS , OS not reached• 1 -year s urvival 8 0 %

Adver s eE vents

• Grade 3 and 4 events acros s all cohorts (n=1 0 0 )• Fatigue 5 %• P yrexia 4 %• Anemia 5 %• Hyperglycemia 3 %

Subbiah et al JCO 2018

Conclusions: Thyroid Cancer

• A number of TKI are available for patients with DTC and MTC • For PTC: Lenvatinib and Sorafenib are the two agents of choice • For MTC: Cabozantinib and Vandetanib are the two agents of

choice • Observation is often a reasonable options for many patients • Treatment has side effects and patient selection is very

important • Management of side effects is essential to good outcome • Consider local therapies when appropriate

Documents

Cancer Medicine & Hematology · 2019. 9. 18. · E. G. I. S. T. E. R. Mandatory. p16. testing . S. T. R. A. T. I. F. Y. T Stage. 1. T1-2. 2. T3-4. N Stage. 1. N0-2a. 2. N2b-3. Zubrod